Gastrointestinal (GI) tract disorders affect the quality of life of millions of men and women in the United States every year. GI tract disorders may involve disturbances of the GI smooth muscle, epithelium, sensory afferent neurons, or central nervous system pathways. In spite of the uncertainty regarding whether central or peripheral mechanisms, or both, are involved in GI tract disorders, many proposed mechanisms implicate neurons and pathways that mediate visceral sensation. Viscerosensory information from the GI tract is relayed by sensory fibers that enter the spinal cord via the dorsal root ganglion (DRG) or project to the nodose ganglion via vagal afferents (Physiology, ed. R. M Berne and M. N. Levy, 1983, CV Mosby Co. St. Louis). A number of different subtypes of sensory afferent neurons may be involved in neurotransmission from the GI tract. These may be classified as, but not limited to, small diameter, medium diameter, large diameter, myelinated, unmyelinated, sacral, lumbar, DRG, vagal, nodose, peptidergic, non-peptidergic, IB4 positive, IB4 negative, C fiber, Aδ fiber, Aβ fiber, high threshold or low threshold neurons.
GI tract disorders have been characterized as structural (or mucosal) GI tract disorders and non-structural (or non-mucosal) GI tract disorders. Structural disorders include inflammatory bowel disorders and non-inflammatory structural GI tract disorders. Non-structural disorders include a variety of disorders classified as functional GI tract disorders.
Inflammatory bowel disorders include a group of disorders that can cause inflammation or ulceration of the GI tract. Ulcerative colitis and Crohn's disease are the most common types of inflammatory bowel disorders, although collagenous colitis, lymphocytic (microscopic) colitis, and other disorders have also been described.
Ulcerative colitis is a chronic inflammatory disorder of unknown etiology afflicting the large intestine and, except when very severe, is limited to the bowel mucosa. The course of this disorder may be continuous or relapsing and may be mild or severe. Medical treatment primarily includes the use of salicylate derivatives, glucocorticosteroids such as prednisone or prednisone acetate and anti-metabolites dependent on the clinical state of the patient. Salicylate derivatives, such as sulphazine or mesalamine, are efficacious in patients with mild cases of the disorder. Glucocorticosteroids and anti-metabolites are efficacious in patients with moderate or severe disease but are associated with a number of side effects. Patients who need chronic doses of glucocorticosteroids or anti-metabolites for control of their disorder eventually undergo removal of the colon surgically to eliminate the disease.
Like ulcerative colitis, Crohn's disease (also known as regional enteritis, ileitis, or granulomatous ileocolitis) is a chronic inflammatory disorder of unknown etiology; however the location and pathology of the disease differ. Crohn's disease typically presents in either the small intestine, large intestine or the combination of the two locations and can cause inflammation deeper into the muscle and serosa located within the intestinal wall. The course of the disorder may be continuous or relapsing and may be mild or severe. Medical treatment includes the continuous use of salicylate derivatives, glucocorticosteroids, anti-metabolites, and administration of an anti-TNF antibody. Many Crohn's disease patients require intestinal surgery for a problem related to the disease, but unlike ulcerative colitis subsequent relapse is common.
Collagenous colitis and lymphocytic colitis are idiopathic inflammatory disorders of the colon that cause watery diarrhea typically in middle-aged or older individuals. Lymphocytic colitis is distinguished from collagenous colitis by the absence of a thickened subepithelial collagenous layer. Bismuth in the form of Pepto-Bismol may be an effective treatment in some patients, although more severe cases may require the use of salicylate derivatives, antibiotics such as metronidazole, and glucocorticosteroids.
Functional GI tract disorders are characterized by presentation of abdominal-type symptoms without evidence of changes in metabolism or structural abnormalities. Disorders that are typically considered under functional disorders include dysphagia, non-ulcer dyspepsia, irritable bowel syndrome, slow-transit constipation, and evacuation disorders (Camilleri (2002) Gastrointestinal Motility Disorders, In WebMD Scientific American Medicine, edited by David C. Dale and Daniel D. Federman, New York, N.Y., WebMD). A prominent example of a functional GI tract disorder is irritable bowel syndrome (IBS), also known by a variety of synonyms, including functional bowel, pylorospasm, nervous indigestion, spastic colon, spastic colitis, spastic bowel, intestinal neurosis, functional colitis, irritable colon, mucous colitis, laxative colitis, and functional dyspepsia. IBS generally leads to abdominal pain and/or discomfort and an alteration in bowel habit with no clear etiology. Diagnosis relies on Rome criteria taking into account all symptoms related to patient presentation. (See, e.g., Drossman et al. (1997) Gastroenterology, 112: 2120). Patients typically present with symptoms consistent with hyperalgesia and allodynia.
At present, treatments for IBS have been largely ineffective, and have included stress management, diet, and drugs. Psychoactive drugs, such as anxiolytics and antidepressants, have been utilized but have limited utility because of the side effect profile. Antispasmodics and various antidiarrheal preparations have also been used but these remain as unsatisfactory remedies to patients with IBS.
Non-ulcer dyspepsia (NUD) is another prominent example of a functional GI tract disorder with no established etiology. Symptoms related to NUD include nausea, vomiting, pain, early satiety, bloating and loss of appetite. Altered gastric emptying and increased gastric sensitivity and distress may contribute to NUD but do not completely explain its presentation. Treatments include behavioral therapy, psychotherapy, or administration of antidepressants, motility regulatory agents, antacids, H2-receptor antagonists, and, prokinetics. However, many of these treatments have shown limited efficacy in many patients.
In addition to the structural/non-structural classification described above, GI tract disorders may also be sub-classified based upon anatomical, physiological, and other characteristics of different portions of the GI tract as described in Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 6th Ed. (W.B. Saunders Co. 1998); K. M. Sanders (1996) Gastroenterology, 111: 492–515; P. Holzer (1998) Gastroenterology, 114: 823–839; and R. K. Montgomery et al. (1999) Gastroenterology, 116: 702–731. For example, acid peptic disorders are generally thought to arise from damage due to acidic and/or peptic activity of gastric secretions and may affect the esophagus, stomach, and duodenum. Acid peptic disorders include gastroesophageal reflux disease, peptic ulcers (both gastric and duodenal), erosive esophagitis and esophageal stricture. Zollinger-Ellison Syndrome may be considered an acid peptic disorder since it typically presents with multiple ulcers due to excessive acid secretion caused by a endocrine tumor. Treatments typically include gastric acid suppressive therapies, antibiotics, and surgery. In some patients, however, these therapies have proven ineffective.
Another sub-classification for GI tract disorders may be drawn between gastroesophageal and intestinal disorders based upon characteristics between different portions of the GI tract as disclosed in Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 6th Ed. (W.B. Saunders Co. 1998); K. M. Sanders (1996) Gastroenterology, 111: 492–515; P. Holzer (1998) Gastroenterology, 114: 823–839; and R. K. Montgomery et al. (1999) Gastroenterology, 116: 702–731. Structural gastroesophageal disorders include disorders of the stomach and/or esophagus where there is no evidence of structural perturbations (including those observed in the mucosa) distal to the pylorus. Dyspepsia (chronic pain or discomfort centered in the upper abdomen) is a prominent feature of most structural gastroesophageal disorders but can also be observed in non-structural perturbations, and has been estimated to account for 2 to 5 percent of all general practice consultations. Structural gastroesophageal disorders include gastritis and gastric cancer. By contrast, Structural intestinal tract disorders occur in both the small intestine (the duodenum, jejunum, and ileum) and in the large intestine. Structural intestinal tract disorders are characterized by structural changes in the mucosa or in the muscle layers of the intestine, and include non-peptic ulcers of the small intestine, malignancies, and diverticulosis. Non-peptic ulcers in the small intestine are typically related to administration of non-steroidal anti-inflammatory drugs. Diverticulosis is a disorder that rarely occurs in the small intestine and most commonly appears in the colon.
Because existing therapies and treatments for GI tract disorders are associated with limitations as described above, new therapies and treatments are therefore desirable.